Naphthyl-and indanylimidazolines



United States Patent 3,287 469 NAPHTHYL- AND INDANYLIMIDAZOLINES JohnHarvey, Jr., Wilmington, Del., assignor to E. I. du Pont de Nemours andCompany, Wilmington, Del., a corporation of Delaware No Drawing. FiledSept. 27, 1963, Ser. No. 312,837 7 Claims. (Cl. 260309.6)

This invention relates to partially reduced naphthylimidazolines and toindanylirnidazolines.

More particularly, the compounds of this invention are partially reduced2-(l-naphthyl)imidazolines and 2-(4- -indanyl)imidazolines.

The disclosure herein should not be taken as a recommendation to use thedisclosed invention in any way without full compliance with US. Food andDrug laws and other laws and governmental regulations which may beapplicable.

The compounds of this invention have useful pharmaceutical propertiesand are useful, e.g., as sedatives, hypnotic agents and somnifacients.They are also usef-ul as potentiators for central nervous systemdepressants. They generally have low toxicity and unexpectedly hightherapeutic ratios.

The partially reduced 2-(1-naphthyl)imidazolines of this invention havethe formula:

The 2-(4-indanyl)imidazolines of this invention have the formula:

l N-CH:

It is essential that the imidazoline group be attached as shown to theunsaturated ring of the reduced naphthyl or indanyl groups.

The compounds of this invention can be prepared by the condensation ofethylenediamine with 5,6,7,8-tetrahydrol-naphthoic acid or4-indanecarboxylic acid, respectively, or lower-alkyl esters of theseacids, such as for example, the methyl ester, ethyl ester, propyl ester,isopropyl ester, butyl ester, pentyl ester, hexyl ester, etc.

The reaction is conveniently carried out by heating the ethylenediamineto about its reflux temperature and adding the appropriate acid or esterto the boiling liquid with subsequent heating at reflux for a suitabletime. Other temperatures may be used, however, with a consequentincrease or decrease in reaction time depending on the particulartemperature and reactants used. Upon completion of the reaction, thereaction mixture is cooled and the product separated in conventionalmanner.

An alternative procedure for preparing the compounds of this inventioninvolves the condensation of the monop-toluenesulfonate salt ofethylenediamine with 5,6,7,8- tetrahydro-l-naphthonitrile or4-indanecarbonitrile. This reaction is conducted similar to thecondensation described above, and the product separated in conventionalmanner.

It is specifically intended to include within the purview of the presentinvention the acid addition and quaternary ammonium salts which theabove compounds form with pharmaceutically acceptable anions. The termpharmaceutically acceptable anion has a definite meaning Patented Nov.22, 1966 to one skilled in the art. Suitable acid addition salts includefor example the tartrate, nitrate, sulfate, hydrochloride, hydrobromide,hydroiodide, acetate, succinate, maleate, citrate, and the like.Suitable quaternary ammonium salts include for example thedimethylsulfate, ethyl bromide, methiodide, propyl chloride, and thelike. The salts may readily be prepared by contacting an etherealsolution of the free imidazoline with the acid or quaternizing materialand separating the resulting salt.

The agents of this invention may be administered alone but are generallyadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tablets orcapsules containing such excipients as starch, milk sugar, certain typesof clay, etc. They may be administered orally in the form of elixirs ororal suspensions which may contain coloring and flavoring agents. Theymay be injected parenterally and for this use may be prepared in theform of sterile aqueous solutions containing other solutes such assaline or glucose in sufficient quantity to make the solution isotonic.For intramuscular administration compositions of the compounds of thisinvention may be prepared in an oil base such as peanut or sesame oil.

The compounds of this invention will be administered in a dosagegenerally of the same or lower order of magnitude as with otherpharmaceutical agents having the same types of desired activity.

In certain instances it may be found that because of their high order ofactivity the optimum dosage of the compounds of this invention will belower than the optimum dosage of other compounds generally recommendedfor the same use. In general, the physician or veterinarian willdetermine the dosage which will be most suitable for a particularapplication, and as might be expected, it will vary with the age, weightand general health of the patient under treatment and with various otherfactors which will be determined by the physician or veterinarian inattendance. When they are administered orally a larger quantity will berequired to produce the same efiect as a smaller quantity givenparenterally. Parental administration of from 0.1 mg. to 250 mg. ofactive agent should be suitable.

The compositions of this invention may take a variety of forms. Variousdiluents may be employed and the percentage of active ingredients may bevaried. It is necessary that an active ingredient form a proportion ofthe composition such that a suitable dosage form will be obtained.Obviously several dosage unit forms may be administered at about thesame time. Although compositions with less than 0.005% by weight ofactive ingredient are suitable, it is preferred to use compositionscontaining not less than 0.005% of the active agent because otherwisethe amount of carrier becomes excessively large. Activity increases withthe concentration of the active agent. The percentage by weight ofactive agent may be 10, 50, 75, or even higher. Dosage unit forms may beprepared with a minor proportion of a carrier and a major proportion ofactive materials and vice-versa.

Administration can be by vapor or spray applications through the mouthor nasal passages, especially for anticongestant eflect.

The following examples are given solely for the purpose of illustrationand are not to be construed as limitations of this invention, manyvariations of which are possible without departing from the spirit orscope thereof.

Example 1 One hundred fifty-seven parts by weight (1 mole) of5,6,7,8-tetrahydro-1-naphthonitrile and 464 parts by 3 weight (2 moles)of ethylenediamine p-toluenesulfonate are mixed and heated at 2002l0 C.for 2 hours. The mixture is then dissolved in aqueous HCl and thesolution washed with ether. The resulting aqueous layer is made basicwith ammonium hydroxide and the solid 2-(5,6,7,S-tetrahydro-l-naphthyl)imidazoliue product is 'oollected on a filter.

Example 2 7 Example 1 is repeated using a corresponding molar amount of4-indanecarbonitrile in place of the 5,6,7,8-tetrahydro-l-naphth0nitrile of that example, to obtain 2-(4-indanyl)imidazoline in like fashion.

The invention claimed is:

1. A compound selected from the group consisting of2-(5,6,7,8-tetrahydro-l-n-aphthyl)-2-imidazoline and 2-(4-indanyl)-2-imidazoline and their non-toxic acid addition and quaternaryammonium salts.

2. 2-(5,6,'7,8-tetral1ydro-l-naphthyl -2-imidazoline.

3. 2-(5,6,7,8-tetrahydro-l-naphthyD-Z-imidazoline hydrochloride.

4. 2-(5,6,7,8-tetrahydro-l-naphthyl)-2-imidazoline hydrobromide.

2- (4-indanyl) -2-imidazoline.

2-(4-indanyl)-2-imidaz01ine hydrochloride. 2-(4-indanyl) -2-imidazolinehydrobromide.

References Cited by the Examiner UNITED STATES PATENTS 6/1954 Craig eta1. 260-3096 1/ 1957 Morren 260-3096 7/1958 Gardocki et a1. 260-30968/1958 Meyer et al. 260565 1/ 1959 Ham et al 260-309.6 3/1962 Kuna et a116765 5/1962 Kuna et al. 167-65 FOREIGN PATENTS 11/ 1950 Austria.

8/ 1939 Switzerland. 5/ 1941 Switzerland.

20 WALTER A. MODANCE, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

N. TROUSOF, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF2-(5,6,7,8-TETRAHYDRO-1NAPHTHYL)-2-IMIDAZOLINE AND2-(4INDANYL)-2-IMIDAZOLINE AND THEIR NON-TOXIC ACID ADDITION ANDQUATERNARY AMMONIUM SALTS.